Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review

Abstract

This evidence-based review addresses the question of whether testing for UGT1A1 mutations in patients with metastatic colorectal cancer treated with irinotecan leads to improvement in outcomes (e.g., irinotecan toxicity, response to treatment, morbidity, and mortality), when compared with no testing. No studies were identified that addressed this question directly. The quality of evidence on the analytic validity of current UGT1A1 genetic testing methods is adequate (scale: convincing, adequate, inadequate), with available data indicating that both analytic sensitivity and specificity for the common genotypes are high. For clinical validity, the quality of evidence is adequate for studies reporting concentration of the active form of irinotecan (SN-38), presence of severe diarrhea, and presence of severe neutropenia stratified by UGT1A1 common genotypes. The strongest association for a clinical endpoint is for severe neutropenia. Patients homozygous for the *28 allele are 3.5 times more likely to develop severe neutropenia compared with individuals with the wild genotype (risk ratio 3.51; 95% confidence interval 2.03-6.07). The proposed clinical utility of UGT1A1 genotyping would be derived from a reduction in drug-related adverse reactions (benefits) while at the same time avoiding declines in tumor response rate and increases in morbidity/mortality (harms). At least three treatment options for reducing this increased risk have been suggested: modification of the irinotecan regime (e.g., reduce initial dose), use of other drugs, and/or pretreatment with colony-stimulating factors. However, we found no prospective studies that examined these options, particularly whether a reduced dose of irinotecan results in a reduced rate of adverse drug events. This is a major gap in knowledge. Although the quality of evidence on clinical utility is inadequate, two of three reviewed studies (and one published since our initial selection of studies for review) found that individuals homozygous for the *28 allele had improved survival. Three reviewed studies found statistically significant higher tumor response rates among individuals homozygous for the *28 allele. We found little or no direct evidence to assess the benefits and harms of modifying irinotecan regimens for patients with colorectal cancer based on their UGT1A1 genotype; however, results of our preliminary modeling of prevalence, acceptance, and effectiveness indicate that reducing the dose would need to be highly effective to have benefits outweigh harms. An alternative is to increase irinotecan dose among wild-type individuals to improve tumor response with minimal increases in adverse drug events. Given the large number of colorectal cancer cases diagnosed each year, a randomized controlled trial of the effects of irinotecan dose modifications in patients with colorectal cancer based on their UGT1A1 genotype is feasible and could clarify the tradeoffs between possible reductions in severe neutropenia and improved tumor response and/or survival in patients with various UGT1A1 genotypes.

Fig. 1

Schematic of the partial UGT1A1 gene showing locations of the polymorphisms of interest for this review in the exon 1 promotor region and in exon 1. First exons are alternatively spliced to common exons to produce UGT isoforms. Adapted from Clin Pharmacol Ther. 2004;75:495–500 and Oncology (Williston Park). 2003;17:52–55.,

Fig. 2

The analytic framework: testing for UGT1A1 mutations in patients with metastatic colorectal cancer (CRC) treated with irinotecan (Camptosar). This schematic shows the analytic framework underlying the current review. The numbers indicate the four key questions contained in Table 1.

Fig. 3

Risk ratios for severe diarrhea among cancer patients treated with Irinotecan by UGT1A1 genotype from six published studies.–, The studies are listed on the x-axis, sorted by the risk ratio comparing rates in heterozygotes (*1/*28) to wild-type individuals (*1/*1) on the left-hand side. The risk ratios for homozygotes (*28/*28) versus wild type is the right-hand side. Bars indicate the 95% confidence interval (CI) with the consensus estimate (All) for the two comparison groups. The dotted line indicates a risk ratio of 1.00 (no difference). The two thin solid lines indicate the consensus estimates for the two groups of 1.40 (95% CI 0.94–2.08) and 1.63 (95% CI 0.64–4.14), respectively.

Fig. 4

Risk ratios for severe neutropenia by UGT1A1 genotype from eight published studies.,– The studies are listed on the x-axis, stratified by heterozygote individuals (*1/*28) versus wild type (*1/*1) on the left-hand side and homozygote individuals (*28/*28) versus wild type on the right-hand side. Two results (Iyer 2002 for heterozygotes, Carlini 2005 for homozygotes) are not shown as the risk ratio could not be computed due to no observations in one or more groups. The bars indicate the 95% confidence interval (CI) with the consensus estimate (All) for the two comparison groups. The dotted line indicates a risk ratio of 1.00 (no difference). The two thin solid lines indicate the consensus estimates for the two groups of 1.82 (95% CI 1.16–2.85) and 3.51 (95% CI 2.03–6.07), respectively.

Fig. 5

Flow diagram showing the derivation of clinical sensitivity and specificity of UGT1A1 genotyping to identify severe neutropenia in a hypothetical cohort of 20,000 white individuals with metastatic colorectal cancer. The clinical sensitivity and specificity are derived using previously reported parameters (e.g., allele frequency, risk ratios), stratified by UGT1A1 genotype. Overall, the clinical sensitivity is 24% with a specificity of 91% (false positive rate of 9%).

Fig. 6

Risk ratios for tumor response by UGT1A1 genotype from two published studies., The studies are listed on the x-axis, with the risk ratios for heterozygote individuals (*1/*28) versus wild type (*1/*1) on the left hand side, and the risk ratios for homozygote individuals (*28/*28) versus wild type on the right hand side. The bars indicate the 95% confidence interval (CI) with the consensus estimate (All) for the two comparison groups. The dotted line indicates a risk ratio of 1.00 (no difference). The two thin solid lines indicate the consensus estimates for the two groups of 1.09 (95% CI 0.83–1.43) and 1.70 (95% CI 1.24–2.33), respectively.

Fig. 7

Graphic display of the quality of evidence for selected components of the current evidence review. For analytic validity, clinical validity, and clinical utility, each of the main components of the evidence review is represented by the text within a box. The quality of evidence is shown by the shading (no shading, inadequate; light shading, adequate; dark shading, convincing).